This is a SBIR Phase I application to develop new iron chelating drugs for prevention and treatment of iron overload-induced bone loss in patients with thalassemia major (TM, a rare disease in the US). Virtually all TM patients are affected by osteopenia and osteoporosis, and these skeletal complications herald and contribute to a general clinical deterioration in TM patients. Unfortunately, there is still no specific and effectve therapeutic for TM-induced bone loss so far. Among others, iron overload and its associated free radical oxidative damage in skeletal tissues have been recognized as major causes of bone loss in TM. However, none of the current chelating drugs (deferoxamine, deferiprone and deferasirox) have yet shown the ability to protect the skeleton from iron deposition and oxidative damage, thus effectively preventing and treating TM- induced bone loss. Therefore, there is an unmet need for the development of new chelating drugs that can target the pathogenesis of TM bone loss. To close this gap, our goal of this SBIR Phase I proposal is to further develop our chelators that have potential as effective therapeutics for bone loss in TM patients. This technology has been protected by two US patents and licensed to NanoMedic, a small University of Utah startup company, for further development towards commercialization. Our hypothesis behind this proposal is that our chelators have the ability to reach the bone and remove toxic iron, thus protecting the bone against iron-associated free radical oxidative damage and consequent bone loss. This novel hypothesis is strongly supported by our pioneering studies. To demonstrate our hypothesis and accomplish our goal, one aim is proposed as follows. Aim. To evaluate the therapeutic efficacy of our chelators in an established iron overload animal model. The levels of iron and oxidative damage in the bone of the chelator-treated animals will be simultaneously measured with our unique electron paramagnetic resonance (EPR) technology. The bone protective capability of the chelator will be evaluated using bone dynamic histomorphometric and computed tomography analyses as well as other techniques. Systemic Fe levels and potential toxicity associated with chelation treatment will also be examined with standard methods. We believe that this Phase I study will demonstrate the proof-of-concept of our chelators as a promising therapeutic candidate, and the deservedness for further development to fulfill an investigational new drug submission to the FDA in the following Phase II study. To our best knowledge, our laboratory is the only one to develop a new specific, effective chelating drug for iron-associated bone loss, and we are confident that such drug development will be successfully accomplished because of our multi-disciplinary expertise in chelating drug development, bone biology, bone drug evaluation and bone EPR technology. We also have confidence that our development will bring new, effective therapeutics into the global market, thus significantly impacting the clinical management of osteoporosis and osteopenia in TM patients, from which an estimated 60-80 million people suffer worldwide.